Background and Relevance: A major obstacle to development of potential anti-cancer agents that contain medium-sized rings is the inability to produce these seven- to ten-member carbocycles efficiently. This proposal addresses a deficiency in strategies to form medium-sized rings. This proposal develops a convergent approach to a class of molecules with broad yet selective anti-cancer and anti-alzheimers activities: the guaianolide sesquiterpenes. The guaianolide sesquiterpenes include dehydrocostuslactone, and thiapsigargin. Dehydrocostuslactone shows cytotoxicities comparable to those of cisplatin in several key cancer cell lines. Thapsigargin promotes cell death in proliferative and quiescent cells including androgen-independent prostate cancer cells, which do not respond to conventional chemotherapy. Thiapsigargin analogues have been accessed through 29-step syntheses, and are more potent than thiapsigargin. Better synthetic methods are necessary to produce these molecular architectures so as to develop cost-effective cancer treatments. The tools we develop herein will be relevant to construction of a range of unrelated cytotoxic compounds that incorporate medium-sized rings. Specific aims: These investigations will develop a Heck-type carbon-carbon cross-coupling involving metal-catalyzed scission of a carbon-activator bond, a hitherto unreported technology. The specific aims of this proposal are to develop (1) the intramolecular Heck-type olefination of activated acyl compounds to forge medium-sized carbocycles; (2) the intramolecular Heck olefination with activated heteroaromatics to assemble medium-sized rings; (3) the intermolecular carbon-carbon coupling of alkenes with activated substrates; (4) the highly-convergent synthesis of seven-membered rings through tandem sequential Heck- type olefinations with activated heteroaromatic ester-type compounds. Study design: The design requirements of this method are dictated by the mechanism for Heck-t5T)e cyclization.. To launch investigations, a simple substrate will be employed to optimize carbon-carbon cross- couplings. Optimal conditions will be applied to more complex substrates to construct the structural scaffolds of potential cancer treatments, including dehydrocostuslactone, thapsigargin and sargassinone. PUBLIC HEALTH RELEVANCE: Carbon-based small molecules are essential tools to prevent, understand, diagnose, and treat disease. A major obstacle to these efforts is our inability to construct these chemicals rapidly and in a cost-effective manner. We plan to develop a new process to connect carbons, which should enable us to assemble currently inaccessible drugs, and chemical probes.